Method and Apparatus for Measurement of Neural Response

ABSTRACT

A method for determining a desired location at which to apply a neural therapy. An array of electrodes is positioned proximal to neural tissue. A stimulus is applied from the array which evokes a neural compound action potential response in the neural tissue proximal to the array. A plurality of electrodes of the array simultaneously obtain respective measurements of the neural compound action potential response. From the measurements of the neural compound action potential response a desired location for a neural therapy is determined.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/726,761 filed Dec. 24, 2019, which is a continuation of U.S. patentapplication Ser. No. 14/117,140 filed Nov. 12, 2013, issued on Feb. 25,2020 as U.S. Pat. No. 10,568,559, which is a national stage ofApplication No. PCT/AU2012/000513, filed May 11, 2012, which applicationclaims the benefit of Australian Provisional Patent Application No.2011901826 filed May 13, 2011 and Australian Provisional PatentApplication No. 2011901817 filed May 13, 2011, the disclosures of whichare incorporated herein by reference in their entireties.

TECHNICAL FIELD

The present invention relates to measurement of a neural response to astimulus, and in particular relates to measurement of a compound actionpotential by using one or more electrodes implanted proximal to theneural pathway.

BACKGROUND OF THE INVENTION

There are a range of situations in which it is desirable to measure acompound action potential (CAP). For example, neuromodulation is used totreat a variety of disorders including chronic pain, Parkinson'sdisease, and migraine. A neuromodulation system applies an electricalpulse to tissue in order to generate a therapeutic effect. When used torelieve chronic pain, the electrical pulse is applied to the dorsalcolumn (DC) of the spinal cord. Such a system typically comprises animplanted electrical pulse generator, and a power source such as abattery that may be rechargeable by transcutaneous inductive transfer.An electrode array is connected to the pulse generator, and ispositioned in the dorsal epidural space above the dorsal column. Anelectrical pulse applied to the dorsal column by an electrode causes thedepolarisation of neurons, and generation of propagating actionpotentials. The fibres being stimulated in this way inhibit thetransmission of pain from that segment in the spinal cord to the brain.To sustain the pain relief effects, stimuli are applied substantiallycontinuously, for example at 100 Hz.

While the clinical effect of spinal cord stimulation (SCS) is wellestablished, the precise mechanisms involved are poorly understood. TheDC is the target of the electrical stimulation, as it contains theafferent Aβ fibres of interest. Aβ fibres mediate sensations of touch,vibration and pressure from the skin. The prevailing view is that SCSstimulates only a small number of Aβ fibres in the DC. The pain reliefmechanisms of SCS are thought to include evoked antidromic activity ofAβ fibres having an inhibitory effect, and evoked orthodromic activityof Aβ fibres playing a role in pain suppression. It is also thought thatSCS recruits Aβ nerve fibres primarily in the DC, with antidromicpropagation of the evoked response from the DC into the dorsal hornthought to synapse to wide dynamic range neurons in an inhibitorymanner.

Neuromodulation may also be used to stimulate efferent fibres, forexample to induce motor functions. In general, the electrical stimulusgenerated in a neuromodulation system triggers a neural action potentialwhich then has either an inhibitory or excitatory effect. Inhibitoryeffects can be used to modulate an undesired process such as thetransmission of pain, or to cause a desired effect such as thecontraction of a muscle.

The action potentials generated among a large number of fibres sum toform a compound action potential (CAP). The CAP is the sum of responsesfrom a large number of single fibre action potentials. The CAP recordedis the result of a large number of different fibres depolarising. Thepropagation velocity is determined largely by the fibre diameter and forlarge myelinated fibres as found in the dorsal root entry zone (DREZ)and nearby dorsal column the velocity can be over 60 ms⁻¹. The CAPgenerated from the firing of a group of similar fibres is measured as apositive peak potential P1, then a negative peak N1, followed by asecond positive peak P2. This is caused by the region of activationpassing the recording electrode as the action potentials propagate alongthe individual fibres.

To better understand the effects of neuromodulation and/or other neuralstimuli, it is desirable to record a CAP resulting from the stimulus.However, this can be a difficult task as an observed CAP signal willtypically have a maximum amplitude in the range of microvolts, whereas astimulus applied to evoke the CAP is typically several volts. To resolvea 10 μV spinal cord potential (SCP) with 1 μV resolution in the presenceof an input 5V stimulus, for example, requires an amplifier with adynamic range of 134 dB, which is impractical in implant systems.

CAP recordings are sometimes made during surgical procedures on thespinal cord, to provide an indication of any potential neurologicaldamage being caused by the procedure. Typically, a site below (caudallyof) the area being operated on is stimulated and recordings are madeabove (rostrally of) the site. A diminishing response, or a change inresponse, is taken to indicate a change in the neurological condition ofthe spinal cord and may indicate that lasting damage has been caused bythe procedure. For example such monitoring is often performed duringscoliosis surgery (straightening a curvature of the spine) to ensurethat the decompression doesn't damage the spinal cord. Somatosensorypotentials are also used for spinal cord monitoring during surgery.These are recorded on the scalp of the patient and are evoked fromstimulation of a peripheral nerve, usually one of the tibial nerve,median nerve or ulnar nerve. Somatosensory potentials can also bemeasured in response to stimulation of the spinal cord. For dorsal rootentry zone (DREZ) lesioning surgery, it has been proposed to take pointmeasurements of evoked potentials in order to identify a suitable sitefor the DREZ lesioning to occur.

Any discussion of documents, acts, materials, devices, articles or thelike which has been included in the present specification is solely forthe purpose of providing a context for the present invention. It is notto be taken as an admission that any or all of these matters form partof the prior art base or were common general knowledge in the fieldrelevant to the present invention as it existed before the priority dateof each claim of this application.

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

SUMMARY OF THE INVENTION

According to a first aspect the present invention provides a method fordetermining a desired location at which to apply a neural therapy, themethod comprising:

-   -   positioning an array of electrodes proximal to neural tissue;    -   applying a stimulus from the array which evokes a neural        compound action potential response in the neural tissue proximal        to the array;    -   using a plurality of electrodes of the array to simultaneously        obtain respective measurements of the neural compound action        potential response; and    -   determining from the measurements of the neural compound action        potential response a desired location for a neural therapy.

According to a second aspect the present invention provides a system fordetermining a desired location at which to apply a neural therapy, thesystem comprising:

-   -   an array of electrodes configured to be positioned proximal to        neural tissue;    -   a control unit configured to cause application of a stimulus        from the array which evokes a neural compound action potential        response in the neural tissue proximal to the array, the control        unit further configured to simultaneously obtain a plurality of        measurements of the neural compound action potential response        from a plurality of electrodes of the array, and the control        unit further configured to determine from the measurements of        the neural compound action potential response a desired location        for a neural therapy.

The present invention thus provides for selecting a neural therapylocation by contemporaneously measuring local neural activity at anumber of sites alongside the array. Simultaneously obtainingmeasurements of the neural response at a plurality of locations avoidsvariations which may arise when measuring responses to differentstimuli, and which may introduce error in comparisons betweensequentially obtained measurements. Moreover, simultaneous measurementsare more rapid than sequentially obtained measurements of the neuralresponse, particularly if electrode relocation is required betweensequential stimuli.

The array preferably comprises a large number of electrodes configuredto obtain simultaneous measurements of a neural compound actionpotential response, in order to yield fine spatial resolution of theneural sensitivity map of the area alongside the array. For example thearray may comprise 24 electrodes arranged in 3 columns and 8 rows, ormore.

In some embodiments, the method of the present invention may be appliedintra-operatively in order to provide intra-operative informationregarding the neural compound action potential response. In someembodiments of the invention, the method may be used for intra-operativeDREZ localization, by generating a neural sensitivity map around theDREZ in order to guide DREZ lesioning. In such embodiments, the DREZlesioning may be performed in progressive increments, iteratively withneural sensitivity mapping, whereby the ongoing neural sensitivitymapping provides a progressive intra-operative gauge of the effects oflesioning. In some embodiments of the invention, the DREZ lesioning maybe performed by RF ablation, applied from the same electrode array as isused for the sensitivity mapping. Such embodiments provide for the samedevice to be used for sensitivity mapping and for lesioning, therebyeliminating the need to remove the measuring tools to allow lesioning tooccur and eliminating errors which may arise in location determinationduring intra-operative re-positioning of the measurement and lesioningdevices. Other applications of the invention could include surgicalmonitoring such as scoliosis surgery, spinal cord tumour, spinal cordhypothermia during aortic surgery, spinal cord ischemia during aorticsurgery, TCE-evoked electromyograms during thoracoabdominal aorticsurgery, or diagnoses such as spinal cord potentials in patients withALS, spinal cord potentials in patients with tabes dorsalis, and spinalcord potentials in patients with spinal tumours.

Still further embodiments of the invention may use the methodintra-operatively in order to optimize the position of an electrode orelectrode array being implanted. In such embodiments the neural responsemeasurements may be obtained from the same array as is being implanted,or alternatively may be obtained from a separate array, with stimulibeing applied by the electrode(s) undergoing implantation. For example,such embodiments may be used for intra-operative positioning of anelectrode array being implanted, laterally relative to the spinal cord,for example in order to align the array with the dorsal horn. Suchembodiments recognise that variations occur in the evoked responseamplitude relative to a lateral distance from the dorsal horn.Intra-operative information may be presented to a surgeon by way of asimple amplitude meter, an audible signal undergoing pitch or volumevariations, or otherwise. Embodiments used for intra-operative electrodepositioning may also include caudorostral positioning of an electrode orarray being implanted, as neural sensitivity mapping will be influencedby inter-segment fibre density variations thereby permittingcaudorostral positioning. The ECAP magnitude and stimulus threshold canvary by a factor of two with varying lateral and caudorostral position.The choice of stimulating electrode can therefore have a profound effecton the power consumption for an implanted stimulator for SCS.Embodiments used for intra-operative electrode positioning may alsoinclude intra-operative positioning of a peripheral nerve stimulator,for example an occipital nerve stimulator.

Additionally or alternatively, in some embodiments the measurements ofthe neural response may be obtained occasionally or on an ongoing basispost-operatively, for example in order to give ongoing guidance as tothe suitability of the site of the neural therapy. Such embodiments mayfurther provide for manual or automated re-fitting of a therapeuticdevice whereby a site of the neural therapy is revised in response tothe ongoing measurements. For example, where an electrode array is usedto apply the neural therapy, a selection of which electrode(s) to use toapply a therapeutic stimulus may be altered in response to the ongoingmeasurements and an updated map of spinal cord sensitivity as measuredat each electrode.

Further embodiments of the invention may provide for post-operativelymapping spinal cord sensitivity to peripheral stimuli, to refine theselection of which electrode (location) in an array to use to applyspinal stimuli. For example, the spinal neural sensitivity map maychange over time in response to changed pathology, or may change inresponse to relative movement between implant and spinal cord whethercaused by device migration or by postural changes.

In some embodiments of the invention, the stimulus is applied repeatedlyand the evoked spinal responses are measured repeatedly, with themeasurements being averaged over a number of such cycles to improve SNRand improve the neural sensitivity map produced.

In further embodiments of the invention, the stimulus may be appliedunder the control of a remote control of the implanted array. Forexample, a peripheral stimulus such as a TENS stimulus may be applied byholding the remote control unit against the desired stimulus site.

The stimulus may be a physical stimulus for example manipulation of anextremity of a person. Additionally or alternatively, the stimulus maybe applied by a transcutaneous electrical nerve stimulator (TENS) at theperiphery. Additionally or alternatively, the stimulus may be anelectrical neural stimulus applied directly to a neural pathway. Thestimulus may be applied by the same electrode array as is used tomeasure the neural response.

According to another aspect the present invention provides a computerprogram product comprising computer program code means to make acomputer execute a procedure for determining a desired location at whichto apply a neural therapy, the computer program product comprisingcomputer program code means for carrying out the method of the firstaspect.

BRIEF DESCRIPTION OF THE DRAWINGS

An example of the invention will now be described with reference to theaccompanying drawings, in which:

An example of the invention will now be described with reference to theaccompanying drawings, in which:

FIG. 1 illustrates an implantable device suitable for implementing thepresent invention;

FIG. 2 illustrates a plurality of simultaneously recorded measurementsof a neural response in an ovine spinal cord as a result of stimulationof the sciatic nerve;

FIG. 3 illustrates the peak to peak amplitude of fast evoked responsesmeasured by multiple electrodes of a paddle array;

FIG. 4 illustrates the variation in evoked response amplitude withlocation along a vertebral segment;

FIG. 5 illustrates the variation with location in sensed amplitude ofmeasurements of a single evoked response from different electrodespositioned along a vertebral segment;

FIG. 6 illustrates the variation in actual amplitude of an evokedresponse, when applied by stimulus electrodes at different positionsalong a vertebral segment;

FIGS. 7 a and 7 b further illustrate caudorostral variations inelectrode sensitivity and recruitment efficiency;

FIG. 8 illustrates the variation in evoked response amplitude withlocation across, laterally of, the dorsal column;

FIG. 9 illustrates measurements of spinal cord evoked potentials usedfor identifying the optimal site for DREZ lesioning;

FIG. 10 is a block diagram of a system incorporating an implant remotecontrol configured for generating TENS or mechanical stimuli; and

FIG. 11 illustrates a map of the dermatomes in a human body.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates an implantable device 100 suitable for implementingthe present invention. Device 100 comprises an implanted control unit110, which controls application of neural stimuli, and controls ameasurement process for obtaining a measurement of a neural responseevoked by the stimuli from each of a plurality of electrodes. Device 100further comprises an electrode array 120 consisting of a three by eightarray of electrodes 122, each of which may be selectively used as eitherthe stimulus electrode or sense electrode, or both.

FIG. 2 illustrates a neural compound action potential response in anovine spinal cord resulting from electrical stimulation of the sciaticnerve, as recorded simultaneously on 6 electrodes. In FIG. 2 , the uppertrace shows 20 ms of each recording, while the lower trace shows about 8ms of the same recordings, all made simultaneously of a single neuralresponse. As can be seen in FIG. 2 , the time of arrival of the neuralresponse is slightly different at each sense electrode, reflecting thetime taken for the neural response to travel between electrodes in thearray 120. As can also be seen in FIG. 2 , the peak-to-peak amplitude ofeach measurement differs somewhat, particularly noticeable in the fastresponse in each measurement during the time period around 2-4 ms afterthe nearby stimulus. Mapping the relative amplitude of the neuralresponse against the location of the respective recording electrodeproduces a neural sensitivity map of the neural tissue adjacent theelectrode array. The neural sensitivity map so obtained by the presentinvention may be beneficial in several applications.

For example, the topographic map of sensitivity may be used to selectthe most sensitive electrodes for stimulation.

Sensing the neural compound action potential response, also referred toherein as the neural response, involves detection of the local fieldpotential generated by the depolarisation of one or more axons along oneor more nerve fibres. In some embodiments of the invention the evokedCAP measurements may be made by use of the neural response measurementtechniques set out in the Australian provisional patent application No.2011901817 in the name of National ICT Australia Ltd entitled “Methodand apparatus for measurement of neural response” from which the presentapplication claims priority. Additionally or alternatively, the neuralresponse measurement may be conducted in accordance with any suitableCAP measurement technique.

Embodiments of the invention may provide for intra-operative monitoringof a neural sensitivity map. One such example is the surgical placementof percutaneous epidural electrodes. This procedure is typicallyperformed under fluoroscopic examination in order to allow the physicianto accurately place the electrode(s). The desired target locationdepends on the extent of coverage and the pain condition which is beingtreated, however in many circumstances the surgeon is aiming to placethe electrode parallel with, and in line with the dorsal horn. Neuralsensitivity mapping in accordance with the present invention can be usedto aid electrode placement, as the evoked response amplitude is highestfor an electrode substantially aligned with and parallel with dorsalhorn. In this embodiment of the invention, surgical guidance is providedby a process in which the electrode is inserted in the vicinity of thetarget location, and pulse parameters of an applied neural stimulus areadjusted to establish a reliable evoked response measurement from theelectrodes being implanted. The magnitude of the evoked response isrepeatedly obtained to allow the neural sensitivity map to be monitoredin real time as the electrode position is manipulated by the implantingsurgeon. With such guidance the surgeon positions the electrode toachieve maximal response amplitude for a constant stimulation amplitude.

In this surgical process, the peak to peak amplitude of the evokedresponse can be displayed for the operating surgeon in a number of ways.A simple amplitude meter can be used or other graphical representationof the electrode location with respect to the spinal cord. The positioncan also be presented to the surgeon in an audible form with pitchand/or volume equating to the relative intensity of the evoked response.

In another embodiment, a neuromodulation system used for stimulation ofperipheral nerves, for example the occipital nerve for the treatment ofchronic migraine, is surgically positioned with the aid of the presentinvention. The evoked response arising from occipital stimuli applied bythe implanted system is measured by sense electrodes, and used to helplocate the position of the occipital nerve. The presence of an evokedresponse indicates the proximity of a nerve, and the strength of theevoked response can be used to intra-operatively fine tune the implantposition.

Still another embodiment provides for an intra- or post-operativeobjective indication of the likely efficacy of spinal cord stimulation,prior to any user trial period. In such embodiments, the presence orabsence of a strong Aβ response in the measurement of the evokedpotential, and the diagnostic information from the neural properties, isused as an indication of the likely efficacy of spinal cord stimulation.Such embodiments may even eliminate the need to conduct trialstimulation periods. In such embodiments the procedure would be: (1)implant electrode array; (2) assess the quality of the neuralsensitivity map and evoked responses, and (3) if acceptable responsesare observed, the clinician can make the choice at this point to proceedto full implantation. Such embodiments recognise that the ability tomeasure the efficiency of Aβ fibre recruitment is directly related tothe outcome of the therapy.

In a further embodiment, the present invention is applied for electrodearray location determination within a spinal segment. The spinal nervesjoin the spinal cord at each vertebral segment. The Aβ fibres enter thedorsal horn (dorsal horn entry zone) DREZ on the dorsal side, projectingfrom the dorsal root ganglia. The fibres cross the vertebrae in a bundleand then project up and down, sometimes as far as a few segments. Theevoked response is proportional to the arrangement and distribution offibres. FIG. 4 illustrates the variation in evoked response amplitudewith location along a vertebral segment. The electrodes are positionedat 7 mm spacings along the array, giving a corresponding capability forposition resolution. Thus, measurement of the evoked response map can beused to locate the electrode both laterally and caudorostrally withrespect to a spinal segment, by referring to the modulation of theresponse along the electrode array arising from the variation in densityof fibres. Thus, obtaining a neural sensitivity map in accordance withthe present invention permits lateral and/or caudorostral implantpositioning.

The relative intensities of the evoked response are related to both theseparation of the electrode from the surface of the spinal cord and theproperties of the fibres being stimulated. The effect of varyingseparation can be accounted for and so the intrinsic measure of thesensitivity of the spinal cord under each of the electrodes can be usedto form a sensitivity map of the spinal cord.

FIG. 5 illustrates the variation with location in sensed amplitude ofmeasurements of a single evoked response from different electrodespositioned along a vertebral segment. As a single ECAP propagates alongthe dorsal columns, the recordings of distal electrodes contain the sametri-phasic morphology observed on the electrodes adjacent to thestimulus electrodes; only delayed in time, as a result of the conductionvelocity, and with a variation in amplitude. The amplitude of theresponses depends on the anatomical location of the recording electrode.This is illustrated in 5, where a stimulation current of 2.75 mA hasbeen applied on electrodes 13-15, and the ECAβ response as sensed ateach other electrode is measured. In general, the electrodes positionedover the mid-vertebral segments (e.g. E10, E6), show larger measuredpotentials than do the electrodes positioned over the intervertebraldiscs (e.g., E8). The propagation direction is antidromic and a diagramindicating the anatomical placement of the electrodes is shown in thelower portion of FIG. 5 . The envelope of the measured responsesgenerally decays with increasing distance from the recording electrodehowever those electrodes located in the areas where there areintervertebral discs demonstrate a pronounced reduction in amplitude incomparison with their neighbors. This map profile is further illustratedin FIG. 7 . Thus, a single stimulus enables a map to be obtained of therelative measurement sensitivity of all non-stimulating electrodes.

FIG. 6 illustrates the variation in actual amplitude of an evokedresponse, when applied by stimulus electrodes at different positionsalong a vertebral segment. Plot 6A shows measured responses when astimulus is applied by the mid-vertebral electrode E2, plot 6B showsmeasured responses when the same stimulus is applied by theintervertebral electrode E9, and plot 6C shows measured responses whenthe same stimulus is applied by mid vertebral electrode E15. Theamplitudes of the measurements of the neural response in plot B are lessthan half those of plots A and C, demonstrating the reduced neuralrecruitment ability of electrode E9 as compared to electrodes E2 and E15because of its disadvantageous position. Mapping the array as shown inFIG. 5 permits such disadvantageously positioned electrodes to beidentified and then omitted from a stimulus regime in order to maximiserecruitment efficiency and conserve battery. In particular it is notedthat similar variability in recruitment efficiency occurs with changesin lateral position relative to the dorsal column, so that optimisingelectrode position in both laterally and caudorostrally allows for powersaving of up to a factor of perhaps 5 or 6, and may also improve deviceefficacy for patients who otherwise experience negligible or reducedbenefit.

To further illustrate this phenomenon, the P2-N1 amplitude (at a fixedstimulation current, and pulse width of 40 μs) for all stimulation sitesalong the electrode array is presented in FIG. 7 , in which orthodromicdata (FIG. 7 b ) are separated from antidromic data (FIG. 7 a ) for allrecording electrodes. Once again the amplitudes of the responsesgenerally reduce with distance from the stimulation electrodes, but theresponses at electrodes 13 and 9 in particular are further reduced fromthis trend line (FIG. 7 a ) due to their disadvantageous intervertebralposition. Similarly, stimulation at electrodes 13 and 9 generated theweakest overall responses (responses 713 and 709, respectively, in FIG.7 b ).

This embodiment of the invention thus recognizes that there aresignificant differences in the relative sensitivities of different areasalong the spinal cord. The electrodes on which the lowest magnituderesponses were recorded also generated the lowest evoked responses whenused as the stimulating electrodes. This may be due to the separationbetween the electrode and the dorsal column fluctuating between thevertebrae as a natural consequence of the anatomy. The distance betweenthe dorsal columns and the electrode is inversely proportional to itseffectiveness. The increase in separation also reduces the responseamplitude.

The amplitude and the excitability will also be affected by changes inthe conductivity of the medium immediately surrounding the stimulatingand recording electrode. Bone resistivity is more than twice that of theintervertebral discs that sit between the vertebral bodies and as aresult the current spread from the stimulating electrodes inintervertebral positions would make recruitment less efficient andconsequently smaller responses are observed.

Another possible explanation for the modulation in the response is dueto the arrangement of the fibers within the dorsal columns. Eachvertebra marks the introduction of new fibers from the correspondingdorsal roots. The excursion that these fibers take, as new laminae arelaid down in the dorsal columns, will affect the position of fibers thatentered the dorsal columns at lower segments. This will result in achange in the position of the fibers within the column and may manifestas a variation in the response amplitudes. Regardless of which reason(s)prove to be applicable, the present embodiment provides for a mapping ofsuch variations and in turn the optimization of a stimulus program forthe device as a whole. Noting that lead migration is a common problem inspinal cord stimulation, reassessing the “signature” response of theamplitude variation as shown in FIG. 7 a could be used to determine thelongitudinal change in the electrode position.

FIG. 8 illustrates the variation in evoked response amplitude withlocation across, i.e. laterally of, the dorsal column, and in particularplots the variation in amplitude (P2-N1) with the lateral electrodeposition. The sense electrode was positioned at a given distancelaterally from the dorsal column, and used to sense evoked responsesarising from a nearby applied stimulus. For each lateral position of thesense electrode, ten successive stimuli of varying amplitude wereapplied and sensed. FIG. 8 shows the measured N1-P2 data for 12different lateral positions (nominated position numbers 13 through 24)of the sense electrode for stimuli of 10 different amplitudes. As can beseen the strength of the sensed response for a given stimulus issignificantly stronger when the sense electrode is positioned in thecentre of the dorsal column, at about position 17, and not laterally toeither side. Delivery of stimuli from position 24 for example wouldconsume significantly greater power to achieve the same therapeuticeffect as compared to stimulating from position 17. Thus, thisembodiment recognises that measurement of the evoked response map, witha suitable laterally configured array such as is shown in FIG. 1 or 3 ,can be used to locate a suitably located electrode laterally withrespect to a spinal segment, by referring to the modulation of theresponse across the electrode array. Alternative embodiments may performthe mapping by applying the stimulus from varying lateral positionswhile sensing from a fixed reference position. Thus, obtaining a neuralsensitivity map in accordance with the present invention permits lateraland/or caudorostral implant positioning and/or stimulus delivery.

In still further embodiments, the topographic neural sensitivity map maybe used as a tool to monitor the function of the spinal cord to optimisesurgical efficacy and minimise neurological side effects, in any one ofa variety of surgical procedures. One such procedure is DREZ lesioning,which selectively destroys the dorsolateral aspect of the spinal cord atthe area of entry of dorsal root fibres to the spinal cord, to produce atherapeutic benefit. DREZ is indicated for the control of medicallyrefractory chronic pain associated with traumatic plexus avulsions. Thelesions are made using one of a variety of techniques, including cuttingwith a surgical blade, through a series of radio frequent lesions, witha DREZ electrode, laser or focused ultrasound. This embodiment providesfor a topographic neural sensitivity map to be obtained fromsimultaneous measurements of a single evoked neural response, to providea guide as to the best location to perform the lesion. FIG. 9illustrates spinal cord evoked potentials and their use in identifyingthe optimal site for DREZ lesioning. In particular, by applyingstimulation at different sites around the DREZ (locations 1 and 3 inFIG. 9 ) produced neural responses. In contrast stimulation at the DREZ(location 2) provoked only weak responses. The site for DREZ lesioningwas identified as corresponding to the site at which no response tostimulation was evoked. The evoked response can be recorded repeatedlyor continuously over the region of the spinal cord lesion with forinstance a paddle array of electrodes. A neurophysiological response mapof the spinal cord can be made by stimulation and recording oncombinations of electrodes. For instance the dead region (area wherethere is a significantly low response over the spinal cord) can bedetermined by scanning the entire array of electrodes with a stimuluspulse and recording for all other electrodes (or nearest neighbour). Amap of the low response region can then be directly visualised from theresponse map.

A further enhancement enabled by this embodiment of the inventioninvolves, after obtaining the required topographic neural sensitivitymap and satisfactorily locating the target lesioning site, connectingthe recording electrodes to radiofrequency (RF) ablation equipment via aswitching mechanism so that the system can automatically select theelectrodes closest to the target lesioning site, and use thoseelectrodes to apply the RF lesioning burst. Incremental lesioning mayfurther be undertaken, with the neural mapping exercise being carriedout on an iterative basis so that the extent of lesioning can be morefinely controlled.

As will be appreciated, the technique of this embodiment is notrestricted to the use of RF lesioning but can use other forms of tissueremoval, for example laser ablation. As discussed previously herein, themeasurement of a map of the locally excited ECAP provides a great dealof information about the fibre properties. This information can be usedin any surgical setting where it is desirable to isolate one type offibre group (with distinct properties) from others for selectivetreatment e.g. by deaxonation. Fine control could be exercised withlaser surgery.

In yet another embodiment of the invention, continuous recording isperformed of evoked responses. The evoked responses can be generatedeither by electrical stimulation of the spinal cord or by electrical ormechanical stimulation at the periphery. This can be used to aid findingthe ideal location for electrical stimulation to produce the optimaltherapeutic effect. The procedure would be as follows:

-   -   1. TENS electrodes or a mechanical stimulator is placed over the        painful area.    -   2. The spinal cord stimulation electrode array is placed in the        epidural space.    -   3. The Evoked Responses are recorded for each electrode, as        illustrated in FIG. 2 , to obtain the neural sensitivity map.    -   4. The stimulation site is selected by reference to the        electrode which measured a target feature. For example the        target feature may be the largest response amplitude, and the        stimulation site location may be chosen to be at that        measurement site or at a site derived by reference to the        measurement site.

To improve the signal to noise ratio the evoked response measurementsare averaged over a number of recording cycles. In order to perform theaveraging the stimulus is a periodically varying signal, with stimulusposition in time known for each stimulus to enable the averagingprocedure. During inter-operative placement the stimulus can begenerated by an external stimulator which is interfaced directly withthe response measurement amplifier to synchronise the timing of themeasurements with the stimulus.

Thus some embodiments of the invention provide for stimulation at theperiphery to locate the best locus of neural excitation. The commonsurgical procedure for implantation of percutaneous spinal cord leadsinvolves a process referred to as trawling. The electrode is placed at ahigher position than required as predicted by the dermatome map and thenthe electrode is slowly moved (pulled back) while stimulating until theconscious patient reports a correspondence between the area ofparaesthesia and pain. Evoked response measurements can be used tolocate the ideal area of stimulation by applying a stimulus over thearea which is painful by suitable means (e.g. a TENS apparatus) and thendetermination of the electrode which measures the largest evokedresponse. The peripheral stimulation provides a means to identify thebest location for the electrode placement and doesn't rely on feedbackfrom the patient. The patient can be in a general anesthetised state (orotherwise incapable of communicating feedback), which may be desirableunder some circumstances

In some embodiments the method of the present invention is configuredfor operation after the time of initial implantation of the electrode,as well as for intra-operative determination of the location forstimulation. For post-operative neural mapping, a spinal cord system isused in conjunction with a remote control (FIG. 10 ) to control thelocation of the stimulation. The remote control communicates with theimplant via wireless communication. Various means may be used to allowthis communication to be done efficiently (e.g. by reducing the numberof times the communication link is polled depending on the activity ofthe system). The patient remote control provides a means to operate orchange parameters stored in the implant so that the user has the abilityto adjust the stimulus to achieve an optimal therapeutic outcomeregardless of changing circumstances.

Lead migration represents a major issue for spinal cord stimulators Leadmovement can result in changes to stimulation parameters or locationhaving to be made to achieve optimal pain relief. This may not be due toa change in the required therapeutic location on the spinal cord, butrather because the lead has moved relative to its original location.Thus, in this embodiment adjustment of stimulus location can be made byselecting alternative programs with the remote control. Alternativelythe above mentioned technique may be used by placing TENS pads or amechanical stimulator over the painful site and using the amplitude ofthe evoked response to locate the new desired site for stimulation.Further the TENS or mechanical stimulator may be incorporated in theremote control unit, the remote control unit ideally being a hand helddevice which when placed against the skin over the painful area,provides a TENS stimulus which induces an evoked response which can bedetected in the spinal cord to provide the necessary neural map.

One difficulty faced in programming any neuro-modulation system is todetermine the locus of stimulation on a perceptual body map. This isbecause, in existing systems, there is no way to standardise thestimulus such that it produces a constant level of recruitment. Varyingthe stimulus amplitude has an effect on both the locus of the perceivedstimulation and on the area covered. Stimulating at fixed point abovethreshold (n·T_(e)) for the Aβ fibres allows stimulation at fixed levelof recruitment. Thus, one embodiment of the invention provides formeasurement of stimulus threshold over multiple electrodes in order tocreate a percept body map. The stimulation threshold for neuralrecruitment can be determined from the peak to peak amplitudes of thefast response. It corresponds to the minimum stimulation level requiredto produce a psycho-physical sensation. An accurate body map relatingpercept with electrode stimulation location can be determined bystimulating each electrode in turn and asking the patient to locate thelocus of perception on a graphical body map (such as shown in FIG. 11 ).The dermatomes shown are each an area of perception on the skininnervated by a single spinal nerve, and thus relate these areas to thecorresponding level where they enter the spinal cord. A body map basedon threshold or other constant recruitment condition provides a means toselect electrodes to achieve the desired level of coverage. Thethresholds can be determined for single electrodes as stimulating sites,or for two electrodes used in parallel as a single site, or any othercombination of electrodes.

The task of the clinician programming the system is to optimise the painrelief through selecting stimulus parameters and location to achievecoverage (matching the area of paraesthesia with area over which thepatient experiences pain). The choice between stimulating at one or twolocations can have an impact on the power consumption of the system.Mapping the percepts at constant Aβ evoked responses allows theclinician and user to quickly identify electrodes which are aligned withthe regions required for pain relief. The differences in percept fordifferent combinations of electrodes provides a guide for lowering powerconsumption. For example, where two electrodes correspond to the sameparaesthesia location, then stimulation on those two together willreduce the power consumption of the device.

Still further embodiments of the invention may provide for the neuralsensitivity map to serve as a diagnostic tool. Routinely, duringassessment of patients for spinal cord stimulation therapy, the patientwill undergo a trial stimulation procedure. This is where the patient isimplanted with a percutaneous lead with an externalised set of contacts.The lead is attached to an external pulse generator and the patient hasuse of the device for several days. At the end of the trial period theclinician and patient assess the performance of the system with regardto pain relief and a choice is made whether or not to proceed with afull implantation. In this embodiment of the invention, the take-homedevice for trial purposes may consist of both a stimulus generator butalso an evoked response measurement and mapping system. The ERT responsemaps recorded during the trial period could be used to adjust thestimulus parameters as described above.

The neural response measurement system of some embodiments of thisinvention may measure amplitude growth functions etc., collected at thetime of surgery and also during the trial stimulation period which,together with subjective performance measures, could be used to developa correlation between the response parameters and the patient outcomes.For instance, there is considerable variation between patients inthreshold response, and there may exist a correlation between thresholdand outcome, where lower thresholds generate better outcomes. There area large number of neurological parameters that can be collected inperforming neural map measures, including amplitude response, conductionvelocity, refractory periods etc. Systematic collection of this dataacross a number of patients will allow analysis for correlation withoutcome.

The intra-operative measurement system may in turn be equipped withalgorithms based on the analysis of past surgeries, trial periods andpatient responses, to inform the clinician at the time of a new surgeryas to the likelihood of a favourable patient outcome. The clinician maythen be given a choice whether to proceed with the full implantprocedure at this time. One special case is if the system records noresponses at all which indicates that any patient benefit is unlikely.

The neurophysiological properties of the spinal cord measured from theepidural space may be important in a number of other diagnosticsituations in which the present invention may be applied. For example itmay desirable to monitor the condition of the spinal cord duringrecovery from back surgery or after back injury.

There are several techniques which are routinely performed in order tooptimally place an electrode during surgery. The procedure is generallyto determine the site for the electrode to be introduced by selecting avertebral level, based on the area of perception of the pain. Thevertebral level is determined from a dermatome map. The surgeon thenplaces the electrode (under fluoroscopy for a percutaneous introducedelectrode array) at the vertebral level corresponding to the identifieddermatome. For paddle style electrodes the array is introduced after alaminectomy is performed.

Some electrodes are more sensitive than others due to their proximity toa higher density of Aβ fibres in the DREZ, a fact illustrated in FIGS. 4and 8 . Anecdotal data from sheep experiments, as well as aconsideration of spinal cord anatomy, suggests that as the epiduralstimulation site shifts laterally from the midline, the chance ofeliciting motor reflexes and other responses of the motor neuronsincreases. For a given stimulus intensity, if the slow responses appearor become larger than previously, this is an indicator that lateralmovement of the electrode has occurred. Further, if the ratio of theslow response to fast response thresholds changes, this may alsoindicate lateral migration. This scenario may lead to undesiredsensation and may need to be rectified. Accordingly, in some embodimentsin which a paddle electrode is used, the stimulation electrodes may bechanged to electrodes which are medial to the current (off-centre)stimulating electrodes. If a single “percutaneous” electrode array isused, the stimulus intensity may be reduced to avoid the undesiredsensation produced, or again the stimulus location may be shifted. Bothof these changes could be made in an automated fashion with a feedbackcontroller, based on neural sensitivity maps obtained in accordance withthe present invention.

In another embodiment the present invention may be applied in relationto dorsal root ganglion (DRG) stimulation and measurement in the spinalcord Direct stimulation of the DRG has been shown to be effective inparaesthesia generation and pain relief for individuals suffering fromchronic pain. Accessing the DRG requires design of specific stimulationelectrodes such as a hook electrode. DRG stimulation is designed torecruit the Aβ fibres present on the outer surface of the DRG. The largediameter fibres, which are more easily stimulated, partition to theoutside of the DRG and these are mainly Aβ. The foramen where the DRGsits is more confined than the epidural space where an electrode isplaced for epidural stimulation of the spinal cord. Because of thisconfinement, fixed stimulation parameters tend to provide a more stableparaesthesia sensation in DRG stimulation as compared to epiduralstimulation. The DRG electrodes are programmed via a standardneuromodulation stimulation paradigm in which location and size ofparaesthesia are adjusted via stimulation parameters to generateparaesthesias which overlap the painful area. This embodiment recognisesthat evoked response measurement in accordance with the presentinvention can be used to optimize the response from DRG electrodesystems similarly as described for other embodiments in the preceding.Such measurements permit optimization of stimulation parameters,optimization of dynamic neural responses and closed loop feedbackcontrol to eliminate variations in delivered therapy. Both sense andstimulus electrodes can be placed directly in the DRG. Alternatively,stimulus electrodes can be placed in the DRG and recordings can be madefrom the spinal columns with electrodes placed in the epidural space.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention as shown inthe specific embodiments without departing from the spirit or scope ofthe invention as broadly described. The present embodiments are,therefore, to be considered in all respects as illustrative and notrestrictive.

1. A method for determining a desired location at which to apply aneural therapy, the method comprising: positioning an array ofelectrodes proximal to neural tissue; applying a stimulus from the arraywhich evokes a neural compound action potential response in the neuraltissue proximal to the array; using a plurality of electrodes of thearray to simultaneously obtain respective measurements of the neuralcompound action potential response; and determining from themeasurements of the neural compound action potential response a desiredlocation for a neural therapy.
 2. The method of claim 1 wherein thearray comprises a large number of electrodes configured to obtainsimultaneous measurements of a neural response, in order to yield finespatial resolution of the neural sensitivity map of the area alongsidethe array.
 3. The method of claim 2 wherein the array comprises 24electrodes arranged in 3 columns and 8 rows.
 4. The method of claim 1when applied intra-operatively in order to provide intra-operativeinformation regarding the neural response.
 5. The method of claim 4,when used for intra-operative DREZ localization, by generating a neuralsensitivity map around the DREZ in order to guide DREZ lesioning.
 6. Themethod of claim 5, wherein DREZ lesioning is performed in progressiveincrements, iteratively with neural sensitivity mapping, whereby theongoing neural sensitivity mapping provides a progressiveintra-operative gauge of the effects of lesioning.
 7. The method ofclaim 5 wherein the DREZ lesioning is performed by RF ablation, appliedfrom the same electrode array as is used for the sensitivity mapping. 8.The method of claim 7, when used iteratively with cortical lesioning, soas to give a progressive measure of the efficacy of incrementallesioning of the origin site.
 9. The method of claim 1, when usedintra-operatively in order to optimize the position of an electrode orelectrode array being implanted.
 10. The method of claim 9, when usedfor intra-operative positioning of an electrode array being implanted,laterally relative to the spinal cord.
 11. The method of claim 9, whenused for intra-operative caudorostral positioning of an electrode arraybeing implanted, relative to the spinal cord.
 12. The method of claim 1when used intra-operatively and wherein intra-operative informationrepresenting the measurements of the neural compound action potentialresponse is presented to a surgeon by way of an amplitude meter.
 13. Themethod of claim 1 when used post-operatively to give ongoing guidance asto the suitability of the site of the neural therapy.
 14. The method ofclaim 13, further comprising determining when manual or automatedre-fitting of a therapeutic device is required, to cause a site of theneural therapy to be revised in response to the ongoing measurements.15. The method of claim 13 wherein a selection of which electrode(s) touse to apply a therapeutic stimulus is post-operatively altered inresponse to an updated map of neural sensitivity as measured at eachelectrode.
 16. The method of claim 1 wherein the stimulus is appliedunder the control of a remote control of the implanted array.
 17. Asystem for determining a desired location at which to apply a neuraltherapy, the system comprising: an array of electrodes configured to bepositioned proximal to neural tissue; a control unit configured to causeapplication of a stimulus from the array which evokes a neural compoundaction potential response in the neural tissue proximal to the array,the control unit further configured to simultaneously obtain a pluralityof measurements of the neural compound action potential response from aplurality of electrodes of the array, and the control unit furtherconfigured to determine from the measurements of the neural compoundaction potential response a desired location for a neural therapy.